Nicorandil 10mg Tablets are indicated in adults for the symptomatic treatment of patients with stable angina pectoris who are inadequately controlled or have a contraindication or intolerance to first-line antianginal therapies (such as beta-blockers and/or calcium antagonists).Nicorandil relaxes coronary vascular smooth muscle by stimulating guanylyl cyclase and increasing cyclic GMP (cGMP) levels (as shown first in our laboratory) as well as by a second mechanism resulting in activation of K+ channels and hyperpolarization.Nicorandil is a medicine used to treat and reduce chest pain caused by angina. It works by relaxing and widening your blood vessels and increasing the blood and oxygen supply to your heart. Your doctor will usually prescribe nicorandil when other heart medicines have not worked or are not suitable for you.

1. “DEVELOPMENT AND EVALUATION OF A BUCCAL
DRUG DELIVERY SYSTEM FOR THE ANTI-ANGINAL
DRUG-NICORANDIL”
Project seminar presentation for
partial fulfillment of the requirements for the
award of
“3rd
semester of Master of Pharmacy”
By :
ASHISH KUMAR TUDU
M.Pharm.(3rd
Semester)
Roll No. – MP0721
Registration No. – 40694/2020
Under the Esteemed guidance of
Ms.PadminiKanhar,M.Pharm.,
Assistant Professor, Department of Pharmaceutics
SCHOOL OF PHARMACEUTICAL EDUCATION AND RESEARCH
BERHAMPUR UNIVERSITY
BERHAMPUR – 760007,ODISHA
2022

2. TABLE OF CONTENTS
SL.NO CONTENTS PAGE
NO.
1 INTRODUCTION
2 LITERATURE REVIEWS
3 AIM & OBJECTIVES
4 PLAN OF WORKS
5 DRUG PROFILE
6 REFERENCES

3. 1. INTRODUCTION
Amongst the various routes of drug delivery, oral route is
perhaps the most preferred to the patient and the clinicians alike.
However, peroral (Jain, 2003) administrations of drugs have
disadvantages such as hepatic first-pass metabolism and enzymatic
degradation within the GI, which that prohibits oral administration
of certain classes of drugs.
Consequently, other absorptive mucosae are considered as potential
sites for drug administration. Transmucosal routes of drug delivery
(i.e., mucosal linings of the nasal, rectal).
Buccal Delivery system
Oral Delivery System
Vaginal delivery system
Rectal delivery system
Nasal Delivery System
Occular Delivery system
1.1 FUNDAMENTALS OF BIOADHESION
Development of an adhesive bond b/w a polymer and biological
membrane or its coating can be visualized as a 2-step process.
(Lenaerts et al., 1990).
 Step 1 – Initial contact b/w the 2 surfaces
 Step 2 – Formation of secondary bonds due to non-covalent
interaction.

4. This process of bond formation attributed to surface of the biological
membrane, surface of the adhesive and the interfacial layer between the two
surfaces. Molecular events that take place in the interfacial layer depend on the
properties of the polymer and membrane.
Bioadhesive polymers
Bioadhesive polymers are classified into 2 main categories.
1. Polymers that are water soluble, linear and random polymer
2. Water insoluble compounds that has swellable networks joined by cross-
linking agents.
There are so many properties associated with bioadhesive property of
polymers.
 Molecular weight, chain length and cross-linking density
 Charges and Ionization
 Hydrophilic group and hydration
 Chain segment mobility
1.2 MECHANISM OF BIOADHESION
Several theories of bioadhesion have been proposed to explain fundamental
mechanisms of attachment (Deryaguin et al., 1997).
a. Electronic theory
The adhesive polymer and mucus typically have different electronic
characteristics when there two surfaces come in contact, a double layer of
electrical charges form of the interface and then adhesion develops due to the
attractive force from e Transfer across the electrical double layer.

5. b. Adsorption Theory
In the adsorption theory, a bioadhesive polymer adheres to mucus
because of two surface forces such as Vander Waals’ forces, hydrogen
bonds or hydrophobic interactions (Kaelbe, 1997).
c. Wetting Theory
Wetting Theory is predominantly applicable to liquid
bioadhesive systems and analyses adhesive and contact behavior in
terms of the ability of a liquid or a paste to spread over a biological
system.
The work of adhesion, ‘Y’ being defined as the energy per cm
2 released when an interface is formed. The work of adhesion is given
by:
Wa = YA + YB + YAB
where A, B refers to biological membrane and the
bioadhesive formulation, respectively.
d. Diffusion Theory
The essence of this theory is that chains of the adhesive and the
substrate interpenetrate one another to a sufficient depth to create a semi
permanent adhesive bond, the penetration rate depends on the diffusion
coefficients of both interacting polymers and the diffusion coefficient is
known to depend on molecular weight and cross-linking density.
(Champion, 1975; Wake, 1978). In addition, segment mobility, flexibility
of the bioadherive polymer, mucus glycoprotein and the expanded nature
of both networks are important parameters that need to be considered. Drug
delivery via the membrane of the oral cavity can be subdivided as follows:

6. 1. Sublingual delivery – which is the administration of drug via the sublingual
mucosae (The membrane of the ventral surface of the tongue and the floor of
the mouth) to the systemic circulation.
2. Buccal delivery - which is the administration of drug via the buccal mucosa
(the lining of the cheek) to the systemic circulation.
3. Local delivery – For the treatment of conditions of the oral cavity,
principally for ulcers, fungal conditions periodontal disease..
1.3 ADVANTAGES OF BUCCAL DRUG DELIVERY SYSTEM
Drug administration via the oral mucosae offers several advantages, (Khanna
et al., 1998).
1. Ease of administration
2. Termination of therapy is easy
3. Permit localization of the drug to the oral cavity for a prolonged period of
time.
4. Can be administered to unconscious patients.
5. Offers an excellent route for the systemic delivery of drugs with high first
pass metabolism, thereby offering a greater bioavailability.
6. A significant reduction in dose can be achieved thereby reducing dose
dependent side effects.
7. Drugs which are unstable in the acidic environment are destroyed by the
enzymatic or alkaline environment of the intestines can be administered by this
route.
8. Drugs which show poor bioavailability via the oral route can be administered
conveniently.
9. It offers a passive system for drug absorption and does not require any
activation.

7. 10. The presence of saliva ensures relatively less amount of water for drug
dissolution unlike in case of rectal and transdermal routes.
11. Systemic absorption is rapid.
12. This route provides an alternative for the administration of various
hormones, narcotic analgesic, steroids, enzymes, cardiovascular agents, etc.
13. The buccal mucosa is highly perfused with blood vessels and offers a
greater permeability than the skin.
14. It allows for the local modification of tissue permeability, inhibition of
protease activity or reduction in immunogenic response. Thus, relative use of
therapeutic agents like peptides, protein and ionized species can be achieved.
15. Therapeutic return concentration of the drug can be achieved more
rapidly.
1.4 LIMITATIONS OF BUCCAL DRUG ADMINISTRATION
Drug administration via this route has certain limitations (Khanna et
al., 1998).
1. Drug, which irritate the mucosa or have a bitter or unpleasant taste or an
obnoxious odor, cannot be administered by this route.
2. Drugs, which are unstable at buccal pH, cannot be administered by this
route.
3. Only drugs with small dose requirements can be administered.
4. Drug contained in the swallowed saliva follows the peroral route and
advantages of buccal route are lost.
5. Only those drugs, which are absorbed by passive diffusion, can be
administered by this route.
6. Eating and drinking may become restricted.

8. 7. There is an ever present possibility of the patient swallowing the tablet.
8. Over hydration may lead to the formation of slippery surface and structural
integrity of the formulation may get disrupted by this swelling and hydration
of the bioadhesive polymer.
1.5 OVERVIEW OF THE ORAL MUCOSA
Fig 1. Cross sectionview of buccalmucosa
The oral mucosa is composed of an outermost layer of stratified
squamous epithelium. Below this lies a basement membrane, a lamina propia
followed by the sub mucosa as the innermost layer. The epithelia is similar to
stratified squamous epithelia, found in the east of the body in that it has a
mitotically active based cell layer, advancing through a number of
differentiating intermediate layers to the superficial layers, were cells are shed
from the surface of the epithelium. The epithelium of the buccal mucosa is
about 40-50 cell layers thick, while that of the sublingual epithelium contains
somewhat fewer. The epithelial cells increase in size and become flatter as they
travel from the basal layers to the superficial layers.
The oral mucosal thickness varies depending on the site, the buccal
mucosa measures at 500-800 µm, while the mucosal thickness of the head and
soft palates, the floor of the mouth, the ventral tongue, and the gingivae measure
at about 100 – 200 cm. The mucosae of areas subject to mechanical stress (the

9. gingivae and hard palate) are keratinized similar to the epidermis. The mucosae
of the soft palate, the sublingual and buccal regions, however, are not
keratinized. (Harris and Robinson, 1992).Non-keratinized epithelia, such as the
floor of the mouth and buccal epithelia do not contain acylceramides and only
have small accounts of ceramide.
They also contain small amounts of neutral but polar lipids,
mainly cholesterol sulphate and glucosyl ceramides. These epithelia have been
found to be consideration permeable to water than keratinized epithelia. (Squier
et al., 1991)
Fig-2. General structure of the oral mucosa
1.5 PERMEABILITY OF THE ORAL MUCOSA
There is considerable difference in permeability between different
regions of the oral cavity. In general, the permeabilities of the oral mucosae
decrease in the order: Sublingual > buccal > palatal. This rank order, however,
is in accordance with the physical characteristics of these tissues, with the
sublingual mucosae, being relatively thin, the buccal thicker and the palatal
intermediate in thickness, but keratinized.
a. Mechanism of Transmucosal Permeation
The majority of drugs move across epithelial membranes, including the
oral epithelia by passive mechanisms which are governed primarily by the

10. laws of diffusion. (Martindale, 2002). In the case of simple diffusion, two
potential routes of material transport across the epithelium are the
Paracellular and Trancellular pathways. The paracellular route involves
the passage of molecules through intercellular space, while the
transcellular route involves transport into and across the cells.
Substances with a high solubility in lipid are
expected to traverse the oral mucosa more easily by moving along, across
the lipid–rich plasma membranes of the epithelial cells, while water-
soluble substances and ions probably more through the intercellular
spaces.
Transmucosal permeation of polar molecules, such as peptide
based pharmaceuticals, may be by way of paracellular route however,
several barriers exist during the course of paracellular permeation.
Fig-2a. Mechanism of Transmucosal permeation
b.Factors Important to Muccoadhesion
The bioadhesive power of a polymer or of a series of
polymers is affected by the nature of the polymer and also the nature of
the secondary media (Duchene et al., 1988).
Polymer related factors
• Molecular Weight,
• Concentration of active polymers,
• Flexibility of polymer chains,
• Spatial conformation.

11. Environment related factors
• pH,
• Applied strength,
• Initial contact time,
• Selection of model substrate surface,
• Swelling.
Fig-3. Schematic Representation of the Absorption kinetics of buccally administered drugs

12. c. Permeation Enhancers
Many compounds have been cited which are used as oral mucosal
permeation enhancers (Shojari, 1998).
Table- 1. List of compounds used as oral permeation enhancers.
d. Muccoadhesive Polymers
Mucoadhesive polymers can be differentiated based on their
adhesive performance.
Table 2. Mucoadhesive polymers classified according to their adhesive performance

13. 1.6 EXPERIMENTAL METHODOLOGY FOR BUCCAL
PERMEATION STUDIES
Before a buccal drug delivery system can be formulated, buccal
absorption/ permeation studies must be conducted to determine the feasibility
of their route of administration, for the candidate drug. These studies involve
methods that could examine in vitro/in vivo buccal permeation profile and
absorption kinetics of the drug. (Shojari, 1998).
IN VITRO METHODS
Using this method, the kinetics of drug absorption was measured.
The methodology involves the swirling of a 25 ml sample of the test solution
for up to 15 minutes by human volunteers followed by the expulsion of the
solution. The amount of drug remaining in the expelled volume is then
determined in order to assess the amount of drug absorbed. The drawbacks of
this method include salivary dilution of the drug, accidental swallowing of a
portion of a sample solution, and the inability to localize the drug solution,
within a specific site (buccal, sublingual or gingival) of the oral cavity.
A feasible approach to achieve absorption site localization is to retain
the drug on the buccal mucosa using a bioadhesive system. Pharmacokinetic
parameters such as bioavailability can then be calculated from the plasma
concentration vs. time profile.
EXPERIMENTAL ANIMAL SPECIES
For in vivo investigations, many researches have used small animals
including rats and hamsters for permeability studies. The rat has a buccal
mucosa, with a very thick keratinized surface layer. The rabbit is the only lab
rodent that has non-keratinized mucosal lining similar to human tissue has been
extensively utilized in experimental studies. The oral mucosa of larger
experimental animals that has been used for permeability and drug delivery
studies include monkeys, dogs and pigs.

14. 1.8 EVALUATION OF NICORANDIL-BUCCAL TABLETS
1. Weight variation test
To study weight variation, 20 tablets of each formulation were weighed
using an electronic balance, and the test was performed according to the official
method as in USP. The weight variation allowed as per USP limit is 7.5%. The
weights of individual tablets were within the USP limits.
2. Drug content assay
The prepared buccal tablets containing Nicorandil was tested for drug
content uniformity as per specifications of IP 1996. Five tablets were weighed
individually, and the drug was extracted in water. The drug content was
determined as described. An accurately weighed amount of powdered
nicorandil granules (100 mg) was extracted with water and the solution was
filtered through 0.45-µ membrane (New Delhi, India). The absorbance was
measured at 262 nm after suitable dilution.
3. Thickness and diameter
Uniform compression force and volume of die fill leads to uniform thickness.
From each batch, 3 buccal tablets were taken and checked with a electronic
thick-ness gauge (Mitutoyo, New Delhi, India). Similarly, three tablets were
taken and checked for diameter using vernier.
4. Hardness
For each formulation, the hardness of 3 tablets were determined using the
Monsanto hardness tester (Cad-mach, Ahmedabad, India), and the average was
calculated.

15. 5. Friability
For each formulation, the friability of 10 tablets were determined using
the Roche friabilator (Camp-bell Electronics, Mumbai, India), respectively.
6. In-vitro drug release studies
The in-vitro dissolution studies were carried out using USP apparatus
type II (Tab-Machines, Mumbai, India) at 75 rpm. The dissolution medium
consisted for the phosphate buffer pH 6.8 (250 ml), maintained at 37°C ± 0.5°C.
The formulated tablets containing Nicorandil equivalent to 3mg and 5mg were
taken and kept in the dissolution medium and the paddle type stirrer was
adjusted to 75 rpm. 5ml aliquot dissolution media was withdrawn at intervals
and volume withdrawn was replaced with fresh quantity of dissolution media.
The drug release at different time intervals (1h, 2h, 3h, 4h, 5h, 6h, 7h, and 8h)
was measured by diode array UV-visible spectrophotometer at 262 nm.
The percentage of Nicorandil dissolved at various time
intervals was calculated and plotted against time.
7. FT-IR compatibility studies
Weighed amount of the drug (3mg) was mixed thoroughly with 100mg
of potassium bromide (dried at 40° -50° C) which was then compressed under
10 ton pressure in a hydraulic press to form a pellet which was then scanned
from 4000 - 400-1cm using FT-IR 410 PC spectrophotometer. The same
procedure was repeated for polymers and formulations. The IR spectrum of
nicorandil was compared with the IR spectrum of formulation.
8. Dissolution kinetics of drug release
The drug release data of nicorandil were fitted to models representing
Zero order (cumulative amount of drug released vs time), First order (log
cumulative percentage of drug remaining vs time), Higuchi’s (cumulative

16. percentage of drug released vs square root of time), and Korsmeyer’s equation
(log cumulative percentage of drug released vs log time) kinetics to know the
release mechanisms. The data were processed for regression analysis using MS-
EXCEL statistical functions. These data indicated that the drug release followed
the diffusion controlled model as described by Higuchi’s square root of time
equation.

17. 2. REVIEW OF LITERATURE
 Aungst et al., (1988) (carried out study with respect to comparison
of the effects of various transmucosal absorption promoters on buccal
insulin delivery. Results concluded that non-ionic surfactants wherein
the hydrophobic and hydrophilic portions are joined through ether
linkage can be effective buccal absorption promoters but that those
with other bonds are not.1
 Paulo et al., (2002) studied on development of buccal formulations
based on chitosan microspheres containing chlorhexidine diacetate.
The micro particles were prepared by spray-drying technique, their
morphological characteristics were studied by SEM and in vitro
release behavior was investigated in pH 7.0 USP buffer.2
 Shein et al., (2000) studied the enhanced bioavailability by buccal
administration of triamicinolone acetonide from the bioadhesive gels
in rabbits. The pharmacokinetics and bioavailability of triancinolone
acetonide were determined to investigate buccal absorption from the
mucoadhesive gels in rabbits. The entrancing affects of sodium
deoxycholate as an enhancer on the buccal absorption of
triamcinolone acetonide from the mucoadhesion gels was evaluated
in rabbits. Buccal administration of tramcinolone accetonide gels
containing sodium deoxycholoate as an enhancer to rabbits showed
a relatively constant, sustained blood concentration with minimal
fluctuations.3
 Wong et al., (1999) formulated and evaluated the controlled release
buccal patches of Eudragit ME4OD, various bioadhesive polymers,
namely HPMC, SCMC and carbopol of different grades, were
incorporated into the patches, to modify their bioadhesive properties
as well as the rate of drug release using metoprolol tartarate as model
drug. The incorporation of hydrophilic polymers was found to affect
the drug release as well as the rate of drug release using metoprolol
tartarate as model drug. The incorporation of hydrophilic polymers

18. was found to affect the drug release as well as enhance the
bioadhesion. Although high viscosity can enhance the bioadhesions
of the patches, they also tend to cause non-homogenous distribution
of polymers and drug resulting in non-predictable deep release rates.4

Michel et al., (1987) carried out preliminary studies of oral mucosal
delivery of peptide deeps. Comparison of plasma levels from buccal
delivery verses i. v. infusion concluded that the buccal route has
substantial potential for administration of peptides.5

Hemant et al., (1999) carried out study to evaluate the gum Hakea
as a sustained released and muccoadhesive component in buccal
tablets following their application to the buccal mucosa of rabbits.
Results concluded that the gum Hakea may not only used to sustain
the release of chlorpheniramine maleate from buccal tablets but also
demonstrate that the tablets are sufficient mucoadhesive for clinical
application.6

Hessel et al., (1989) carried cut comparison b/w bioavailability of
prochlorperazine by IM, peroral and buccal routes. Final result
concluded that elimination half-life was the least, with the buccal route
and steady state plasma levels could be achieved using only 60% of
the oral dose on buccal administration.7

Sathish et al., (1986) carried out study with respect to enkephelin
hydrolysis in homogenates of various absorptive mucosae of the
albino rabbit in order to assess similarities in rates and involvement
of amino peptidases. Results concluded that the same enzymatic
barrier to en kephalin absorption possibility exists in both the oral and
non-oral mucosae.8

Laila et al., (1992) carried out study with respect to buccal absorption
of Ketobemide and various ester prodrugs in the rat. Results
concluded that all prodrugs show an increased extend of absorption
relative to that of the parent drug.9

19. 
Patel et al., (2006) prepared buccal adhesive patches containing 20
mg of propanolol hydrochloride using solvent casting method.
Patches were prepared at different ratios of PVP K-30 which generally
enhances the releasing rate and evaluated for various
physicochemical characteristics such as weight variation, drug
content conformity, folding endurance, surface pH, mucoadhesive
strength, ex-vivo residence time, in vitro drug release and in vitro
buccal permeation study. Patches exhibited sustained release over a
period of 7 hours. The mechanism of drug release was found to be
non-ficikian diffusion.10

Nina et al., (2005) studied the enhanced bioavailability by buccal
adminstration of PACAP (Pituitary adenylate cyclase – activating
polypeptide). A strong mucoadhesive chetosaricthiogloycolic acid
(TG A) conjugate in combination with reduced glutathione (GSH) on
permeation of PACAP across buccal mucosa were used. Release
studies indicated that a controlled release can be provided from
tablets consisting of chitosan – TGA at a pH of 5, whereas more than
twice as much was released from chitosan TGA tablets pH4.
Combination of permeation enhancing properties, controlled drug
release and muccoadhesion character, chitosan – TGA conjugates
represent a promising tool for buccal administration of PACAP.11

Reinhold et al., (1989) developed and evaluated buccoadhesive
patches, consisting of two ply laminates of an impermeable backing
layer and a hydrocolloid polymer layer containing the drug. Patches
were prepared by a casting procedure using various aqueous
solutions of drugs and hydrocolloid polymers and subsequent drying.
The polymers used were hydroxyl ethyl cellulose, hydroxyl propyl
cellulose, polyvinyl pyrollidone and polyvinyl alcohol. Adhesion to the
mucosal surface was established by interactions of the swollen

20. polymer and buccal mucosal layer. A wide range of controlled drug
release rate can be achieved by polymer dissolution kinetics.12

Smart et al., (1991) developed an in vitro method for assessment of
the adhesive force between a disc of test material and a model mucus
membrane and the method has reproducibility. It was concluded that
only a small force is required to retain a dosage form within the buccal
cavity. Carbopol 934P and EX55 (Polycarbophil) formed the most
stable adhesive bond which remained intact for 8 hours.13

Juan Manuel et al., (2002) designed a two layered mucoadhesive
tablet containing nystatin for the treatment of oral candidosis. Lactose
CD, Carbomer (CR), hydroxyl propyl methyl cellulose (HPMC) was
used as excipients. Properties such as in vitro mucoadhesion, water
uptake, front movements and drug release were evaluated. The
mixture CB: HPMC, 9:1 showed good in vitro mucoadhesion. A
swelling –diffusion process modulates the release of nystatin from this
layer. A non-fickian kinetic was observed.14

Varshosaz et al., (2002) prepared buccoadhesive controlled release
tablets. The tablet contained 30mg of nifedipine and various amount
of carboxymethylcellulose (CMC), carbomer (CP),
polyvinylpyrolidone (PVP), polyvinyl alcohol (PVA), hydroxy propyl
methyl cellulose (HPMC). The highest adhesion force was observed
in 8:2 ratio of CP: CMC and 35%CP adhered for over 8 hours to the
upper gum of 6 healthy human volunteer and a good correlation (r2
=0.989) was observed between drug released in vitro and in vivo.15

Desai et al., (2004) evaluated the mechanism of absorption of
propanolol hydrochloride through porcine buccal mucosa. The tablet
was prepared in a specially designed and fabricated punch. HPMC
and Carbopol 934P were used as polymers. The tablets were

21. evaluated for weight uniformity, friability, hardness, swelling,
mucoadhesive strength, in vitro drug release, stability and in vitro
acceptability. The order of release was by non – fickian diffusion and
first order kinetics. In vivo studies indicated that tablet was
comfortable in oral cavity, not heavy and did not cause any side
effects.16

Ikinci et al., (2004) developed a bioadhesive buccal tablet for delivery
of nicotine. The bioadhesive polymers, carbomer (Carbopol 974P NF)
and alginic acid sodium salt (NaAlg) were used in combination with
HPMC at different ratios. Magnesium carbonate was added as a pH
increasing agent, in vitro studies and bioadhesion studies were
carried out and found that they released nicotine for 8 hours period
and remained intact except for the formulation containing CP: HPMC
at 20:80 ratio.17

Kashappa et al., (2004) prepared and evaluated a novel buccal
adhesive system (NABS) containing propanolol hydrochloride using
hydroxy propyl methyl cellulose (HPMC), Carbopol 934P. A special
punch was fabricated and used while preparing an NBAS.NBAS was
evaluated by weight uniformity, thickness, hardness, friability,
swelling, mucoadhesive strength, in vitro drug release, and in vivo
human acceptability studies. It was concluded that NBAS is superior,
novel system that overcomes the draw back associated with the
conventional buccal adhesive tablet.18

Park et al., (2004) evaluated some naturally occurring
bioincompatible materials such as xanthan gum, karaya gum, guar
gum and glycol chitosan as mucoadhesive controlled release
excipients for buccal drug delivery. Tablets were prepared in a range
of 0-50% of gum, in which glycol, chitosan produced the strongest
adhesion, but concentration greater than 50% w/w are required to

22. produce a non-erodible matrix that can release for over 4 hours and
swelling properties of tablets were found to know the ability of the
material to produce sustained release.19

Vijayaraghavan et al., (2004) studied the effect of formulation
variables on the buccal absorption of a low dose of nifedipine (ND)
which was done firstly to determine the influence of the incorporation
of natural flax seed polymer (FSP) on bioavailability of ND after
peroral administration with buccal administration. Formulation
contains 10mg of ND and 10, 20, 30, 40mg of FSP as well as peroral
administration with buccal of a formulation of 10mg of ND alone. In
vitro study carried out in pH (6.8) phosphate buffer and bioavailability
studies were carried out in 9 male healthy volunteer. A HPLC method
was used to determine the plasma concentration. Bioavailability was
improved with 10mg and 30mg of FSP than ND alone. The inclusion
of flax seed polymer into the formulation resulted in increase in
bioavailability due to increase in adhesion and faster release
characteristic of the polymer.20

Jamakandi et al., (2009) investigation aimed at evaluating the
possibility of using different polymeric grades of hydroxypropyl methyl
cellulose for the development of transdermal drug delivery systems of
nicorandil, an anti-anginal drug. Prepared matrix-type patches were
evaluated their physiochemical characterization followed by in vitro
evaluation. Selected formulations were subjected for their ex vivo
studies on porcine ear skin.21

Shaila Lewis et al., (2006) formulated mucoadhesive tablets for
buccal administration of nicotine. Three types of tablets were
developed each containing two mucoadhesive components (HPMC
and Sodium Alginate), (HPMC and Carbopol), (Chitosan and Sodium
Alginate). For each of these types, batches were produced changing

23. the quantity of polymers resulting in nine different formulations. The
tablets were evaluated for release pattern and mucoadhesive
performance. Pharmacokinetic studies were conducted in smokers. A
peak plasma concentration of 16.78±2.27 mg was obtained in two
hours, which suggests potential clinical utility in Nicotine replacement
therapy.22

24. 3. AIM AND OBJECTIVES
The scope of any formulation primarily focuses on safety and efficacy of the
drug delivery system. Now the focus has been slightly moved to the patient’s
convenience and acceptance, where still the safety and efficacy remain
integrated with design. Recent research efforts through out the world have
resulted in significant development of novel drug delivery systems.
In recent years, there has been increasing interest in the use
of bioadhesive polymers to control the delivery of biologically active agents
systemically or locally. These bioadhesive systems are useful for the
administrative of drugs, which are susceptible to extensive gastro intestinal
degradation and first pass metabolism. Bucolic adhesive system appears to be
attractive because it avoids significant limitations of traditional routes of drug
administration such as poor absorption, enzymatic degradation and first pass
metabolism.
Buccal delivery necessitates the use of mucoadhesive polymer as
their dosage forms should ideally adhere to the mucosa and withstands
salivation, tongue movement and swallowing for a significant period of time.
The objective of the present study was to formulate a suitable drug
delivery system through the buccal mode, for the long term treatment and
prevention of angina pectoris.
Hypertension and angina pectoris, the most common cardiovascular diseases,
require constant monitoring. The first therapeutic drug shown to possess an
ability to hyperpolarize smooth muscle cell membranes is nicorandil, a potent
coronary vasodilator (Frydman et al., 1989). Although nicorandil is one of the
emerging molecules is the case of hypertension and angina, successful
treatment means maintenance of blood pressure at a normal physiological level,
for which a constant and uniform supply of drug is desired (Leonetti et al, 1989,
Camm et al, 1989).

25. Buccal delivery of drugs provide an attractive alternative to the oral
route of drug administration, particularly in overcoming deficiencies associated
with the latter mode of administration problems such as high first pass
metabolism, drug degradation in harsh gastrointestinal environment can be
circumvented by administering a drug via buccal route.
Moreover, buccal drug delivery offers a safer method of drug utilization,
since drug absorption can be promptly terminated in case of toxicity by
removing the dosage form the buccal cavity (Wong FC et al., 1999). It is also
possible to administer the drug to patients, who cannot be dosed orally to
prevent accidental swallowing.
Buccal releases of nicorandil is enabled so that it can be retained
in the oral cavity for desired duration and localize the dosage form in a specific
region and control the release rate of drug.

26. 4. PLAN OF THE WORK
The work entitled, “DEVELOPMENT AND EVALUATION OF A
BUCCAL DRUG DELIVERY SYSTEM FOR THE ANTI-ANGINAL
DRUG-NICORANDIL” is being planned in an aim to achieve the objective
described earlier.
Phase I
1. Literature survey.
2. Identification of the objective for the current study.
3. Optimization of the methodology
Phase II
1. Preparation of standard graph for the drug.
2. Preparation of nicorandil buccal tablets by direct compression method.
• Method 1- Buccal tablet with coated backing layer of ethyl cellulose.
• Method 2- Bilayered buccal tablet with backing layer of ethyl cellulose.
3. Evaluation of the physical characteristics.
3.1. Compatibility study using Infra Red (IR) spectroscopy.
3.2. Tablet assessed with respect to physical parameters such as friability
studies, FT-IR Studies, Swelling studies and swelling Index, tablet thickness,
weight variation test, hardness and n-vitro drug release.
4. Drug content analysis.
5. Dissolution Kinetics of drug.
Phase III
1. Compilation and preparation of reports.

27. 5. DRUG PROFILE
Nicorandil
Nicorandil is one of the emerging molecules in the case of hypertension and
angina and behaves as a potent coronary vasodilator.
Chemical name
2-[(pyridin-3-ylcarbonyl) amino] ethyl nitrate
Empirical formula
Chemical Structure:
Fig : 4. Structure of Nicorandil
Mol. mass
211.175 g/mol
Characteristics
White or almost white powder. Freely soluble in water, acetone
and chloroform.

28. 5.1 PHARMACOLOGY
Nicorandil, a drug approved for the treatment of ischemic heart
disease, has dual properties. The intrinsic mechanism of the drug (selective
activation of K+ ATPchannels at the sarcolemmal and mitochondrial level)
allows coronary and peripheral vasodilatation with subsequent reduction of
preload and afterload. Secondly, because of the role K+ ATPchannels in
ischemic preconditioning, nicorandil have been attributed cardio protective
effects.
Nicorandil acts by relaxing the smooth muscle of the blood vessels,
especially those of the venous system. It does this through two methods. Firstly,
by activating potassium channels, and secondly by donating nitric oxide to
activate the enzyme guanylate cyclase. Guanylate cyclase causes activation of
GMP leading to both arterial and venous vasodilatation. As it is selective for
vascular potassium channels, it has no significant action on cardiac contractility
and conduction.
Although it can dilate the coronary vessels of a healthy
individual, its effects on the coronary vessels of someone with ischaemic heart
disease will be little as they will already be completely dilated. As it couples
arterial dilation along with venodilation, it reduces the preload and the afterload
of the heart.
5.2 INDICATIONS
 Angina Pectoris,
 Hypertension,
 Congestive heart failure.
5.3 PHARMACOKINETICS
 Onset of Action -30min - 60 min
 Cmax -90 min

29.  Protein binding- 20-25%
 Metabolism –denitration of the molecule into the nicotinamide pathway,
 Elimination Half-life-2 hours
5.4 SIDE EFFECTS
Common side effects include flushing, palpitation, weakness,
headache, mouth ulcers, nausea and vomiting. More recently peri-anal, ileal and
peri-stomal ulceration has been reported as a side effect. Anal ulceration is now
included in the British National Formulary as a reported side effect.
5.5 STABILITY
Store below 25°C. Protect from light and moisture.
5.6 CONTRAINDICATIONS AND PRECAUTIONS
Contraindications
Nicorandil is contraindicated in patients with cardiogenic shock,
left ventricular failure with low filling pressures and in hypotension. It is also
contraindicated in patients who have demonstrated an idiosyncratic response or
hypersensitivity to nicorandil. Due to the risk of severe hypotension, the
concomitant use of Ikorel and phosphodiesterase 5 inhibitors (e.g. sildenafil,
tadalafil, vardenafil) is contraindicated.
Pregnancy implications
Animal studies have not shown drug related teratogenic or primary
embryo toxic effects on animal fetuses; however comparative studies have not
been done in humans. Use only when benefit outweighs potential risk in a
pregnant woman.

30. 5.7 DRUG INTERACTIONS
Drug –drug combinations
No pharmacological or pharmacokinetic interactions have been
observed in humans or animals with beta-blockers, digoxin, rifampicin,
cimetidine, acenocoumarol, a calcium antagonist or a combination of digoxin
and furosemide. Nevertheless, there is the possibility that nicorandil may
potentiate the hypotensive effects of other vasodilators, tricyclic
antidepressants or alcohol.
Gastrointestinal perforations in the context of concomitant use
of nicorandil and corticosteroids have been reported. Caution is advised when
concomitant use is considered.

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